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Nearly five decades have transpired since the advent of transvenous right ventricular apical (RVA) pacing, during which time millions of paced patients have derived significant benefit with regard to amelioration of symptoms and longevity. Recent studies, however, suggest that this technique may indeed be nonphysiologic by promoting cardiac dyssynchrony and compromising hemodynamic function (1–4). This has led to a consideration of alternative approaches to cardiac pacing (5–7).

In 1925, Wiggers (8) first demonstrated acute left ventricular (LV) dysfunction from RVA pacing in animals, subsequently shown to result from slower transmyocardial conduction as opposed to the normally rapid ventricular activation seen during sinus rhythm or atrial pacing in the setting of intact atrioventricular (AV) nodal/Purkinje conduction (9). Myofibrillar disarray (10) and increases in intramyocardial catecholamine concentrations (11) have also been observed in association with RVA pacing. Early studies in humans demonstrated pacing-induced cardiac dyssynchrony as assessed by radionuclide angiography, resulting in a deterioration in cardiac performance (12). These findings have been substantiated by more recent evaluations of young patients subjected to long-term RVA pacing with consequent LV dilation, dysfunction, and deleterious remodeling (13,14). Depression in LV ejection fraction (15) and myocardial perfusion defects (16) may extend over time.

A number of large scale trials have also highlighted the potentially detrimental effect of RVA pacing on cardiac function and patient symptomatology. Thus, Andersen et al. (17) examined 225 patients with sick sinus syndrome, predominantly New York Heart Association (NYHA) functional class 0 to II, randomized to single-chamber atrial or ventricular pacing and found a higher incidence of congestive heart failure (CHF) in the latter group, evident only upon longer-term follow-up (17). In the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial, implantable cardioverter defibrillator (ICD) patients with already depressed cardiac function were randomized to DDDR pacing at a relatively short AV interval versus ventricular backup pacing at 40/min; increased RVA pacing observed in the former group was associated with a significantly higher incidence of new or worsened CHF (1). Further analysis demonstrated that the percent right ventricular pacing was predictive of the outcome of death or CHF hospitalization in this trial (4). Similar results were observed in the subset of Multicenter Automatic Defibrillator Implantation Trial (MADIT)-II ICD patients with an ejection fraction ≤30% who were predominantly RVA-paced (3). The Mode Selection Trial (MOST) randomized 2,010 sinus node dysfunction patients and a preserved ejection fraction to dual chamber versus RVA pacing and found a reduction in signs and symptoms of CHF dual-chamber patients (18). However, when Sweeney et al. (2) subsequently examined a subset of 1,339 MOST study patients with a normal baseline QRS duration, they found that a higher cumulative percent RVA paced rhythm was strongly predictive of CHF hospitalization regardless of whether these patients were programmed to DDDR or VVIR pacing.

As a result, alternatives to RVA pacing have been considered. Minimizing RVA pacing may be attempted by programming extended AV delay, AV search hysteresis, or minimum ventricular pacing algorithms that search for and promote intrinsic AV conduction (6,19). Right ventricular outflow tract pacing has been utilized, with mixed results (20). Upgrade from RVA pacing to biventricular (BiV) pacing has been associated with improvement in LV function and alleviation of CHF (21–23).

This issue of the Journalis noteworthy for presenting two papers (24,25) on prophylactic usage of unconventional pacing sites to minimize cardiac desynchronization in patients with standard pacing indications. They are both crossover, blinded, and randomized studies that, despite a small patient sampling, demonstrate significant functional and symptomatic improvement compared with conventional RVA pacing.

In the first study, Occhetta et al. (24) report on 16 patients with chronic atrial fibrillation (AF) and narrow QRS duration who underwent AV node ablation. All patients received both RVA pacing leads as well as active fixation leads placed to allow for direct His-bundle pacing or para-Hisian stimulation. Selective His-bundle pacing was first described in dog preparations by Scherlag et al. (26). In a feasibility study, Deshmukh et al. (27) demonstrated that direct His-bundle pacing was a viable approach for permanent cardiac pacing in patients with dilated cardiomyopathy. This technique coupled with rate control (achieved pharmacologically or via AV node ablation) was successful in reducing LV dimensions and improving cardiac function. It remains unclear how much of the improvement reflected His-bundle pacing versus rate control in the setting of a tachycardia-mediated cardiomyopathy: there was no RVA pacing limb for comparison. Subsequently, these workers did assess a small subgroup of cardiomyopathy patients who also received a lead for RVA pacing; in a noncrossover, nonblinded evaluation they demonstrated increased cardiopulmonary reserve with direct His-bundle pacing (28). In contrast, the current work by Occhetta et al. (24) examined patients predominantly with preserved cardiac function at baseline (ejection fraction >50% in the majority with a mean ejection fraction of 52% for the group), and employed an RVA pacing control mode. They convincingly demonstrated a marked improvement in multiple parameters when His-bundle or para-Hisian pacing was compared with RVA pacing: interventricular electromechanical delay, NYHA functional classification, quality-of-life scores. Although promising, His-bundle lead placement is technically challenging. It is important to differentiate sites that allow true para-Hisian pacing from those that indirectly capture the His bundle (28), and potential applicability to patients with intraventricular conduction delay is unknown. It remains unclear whether there is incremental benefit in patients with greater preexistent LV dysfunction.

In the study by Kindermann et al. (25), BiV pacing was prospectively evaluated as an alternative to RVA pacing in 30 patients with a range of bradycardic conditions; the majority also had left bundle branch block. This was a very sick cohort with mean NYHA functional class 3 and mean LV ejection fraction of 26%. There are potentially confounding variables. Thus, half of the patients had right ventricular leads implanted in the septum and the remainder in the apex; of the coronary sinus leads, one third were placed in the anterolateral position. Despite efforts at cardioversion during the lead-in period, some patients remained in AF. Rate-adaptive pacing was not universally employed. Despite these limitations, when compared with RVA pacing, BiV pacing resulted in significant reductions in LV volumes, N-terminal pro-B-type natriuretic peptide levels, and quality-of-life scores, while improving LV ejection fraction and exercise capacity. This differs from results obtained by Brignole et al. (29) who found little or no added benefit of LV or BiV pacing when compared with RVA pacing in AF patients undergoing AV junction ablation. It is, however, consonant with findings obtained by the Left Ventricular-Based Cardiac Stimulation Post-AV Nodal Ablation Evaluation (PAVE) study, in 184 AF patients with AV node ablation, in whom BiV pacing resulted in improvement in 6-min walk and LV ejection fraction compared with RVA pacing when prospectively evaluated (30).

Given the long track record associated with RVA pacing, it may be premature to abandon conventional pacing in favor of alternative sites. Certainly, additional prospective randomized clinical trials are warranted (31). It is of interest that the recently published United Kingdom Pacing and Cardiovascular Events (UKPACE) randomized trial of 2,021 patients with high-grade AV block reported only a 3.2% subsequent annual event rate for heart failure in single-chamber pacing and 3.3% rate for dual-chamber pacing—no significant difference in a group of patients in whom nearly three quarters had baseline NYHA functional class II or III (32). There remain too many unexamined variables, such as how preexistent structural heart disease may impact upon pacing mode selection. There has been some impression, for example, that RVA pacing may be more deleterious in patients with chronic LV dysfunction (25,33,34). Equally uncertain is how underlying indication for pacing may affect the choice of pacing modality. In the Pacemaker Selection in the Elderly (PASE) trial, for example, quality-of-life benefits associated with dual-chamber pacing compared with RVA pacing were primarily observed in patients with sinus-node dysfunction (35). It is unclear, therefore, whether certain subsets of patients (as opposed to all patients) may be identified as deriving particular benefit from alternative site pacing.

Beyond this, other issues must be addressed in advance of the widespread adoption of these techniques in patients who require pacemaker therapy. Lead delivery systems need to be refined, and training for implanters must rise to the occasion (36). Sufficient implant volumes and implanter proficiency for alternative site pacing must be demonstrated to ensure acceptable patient outcomes as expanding guidelines evolve. Cost-effectiveness is always a consideration. Ultimately, we must choose to be “selective” in our choice of pacing modality (5) by individualizing therapy based on a number of clinical and nonclinical variables. For some patients, the once-preferred right ventricular apex may become an “alternative” site, and what was once conventional may become unconventional.

Footnotes

↵⁎ Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.

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